Process for preparing a cyclic amino acid anticonvulsant compound

ABSTRACT

An improved process for the preparation of a cyclic amino acid by a novel synthesis is described where benzonitrile is treated with an alkali metal and an amine under Birch reduction conditions to generate in situ an anionic intermediate which is alkylated with an α-haloacetic acid moiety which is subsequently converted to the desired product, as well as valuable intermediates used in the process.

This application is a divisional of application Ser. No. 09/647,401, filed Nov. 14, 2000, which is a 371 of PCT/US98/19359, filed Nov. 14, 2000 which claims the benefit of priority of provisional application Ser. No. 60/061,383, filed Oct. 7, 1997, which applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

U.S. Pat. Nos. 4,024,175 and 4,087,544, which are herein incorporated by reference, disclose novel cyclic amino acids of Formula A

wherein R₁ is a hydrogen atom or a lower alkyl radical, and n is 4, 5, or 6 and the pharmacologically compatible salts thereof.

The compounds disclosed in the above United States patents are useful for the therapy of certain cerebral diseases, for example, they can be used for the treatment of certain forms of epilepsy, faintness attacks, hypokinesia, and cranial traumas. Additionally, they bring about an improvement of cerebral functions, and thus are useful in treating geriatric patients. Particularly valuable is 1-(aminomethyl)-cyclohexaneacetic acid (gabapentin).

Gamma-aminobutyric acid (GABA) is an inhibitory amino acid found in the mammalian central nervous system (CNS). It has been reported that dysfunction with GABA neurotransmission in the CNS may contribute or even cause psychiatric and neurological diseases such as epilepsy, schizophrenia, Parkinson's disease, Huntington's Chorea, and dyskinesia (Saletu B., et al., International Journal of Clinical Pharmacology, Therapy and Toxicology, 1986;24:362-373). Gabapentin was designed as a GABA analog that would cross the blood-brain barrier. Gabapentin was found to have anticonvulsant and antispastic activity with extremely low toxicity in man.

U.S. Pat. No. 5,084,479 discloses the use of gabapentin in neurodegenerative disorders. U.S. Pat. No. 5,025,035 discloses the use of gabapentin in depression. U.S. Pat. No. 5,510,381 discloses the use of gabapentin in mania and bipolar disorders.

The aforementioned compounds of Formula A including gabapentin have been prepared from a compound of formula

wherein R₂ is an alkyl radical containing up to eight carbon atoms, and n is as defined above by well-known standard reactions such as, for example, the Hofmann, Curtius, or Lossen rearrangements into the amino derivatives of Formula A. Although these reactions provide the target compounds, they require a large number of synthetic steps and in some cases involve potentially explosive intermediates.

U.S. Pat. No. 4,152,326 discloses cyclic sulphonyloxyimides of formula

wherein R₂ is a saturated, straight-chained, branched or cyclic lower aliphatic radical or an unsubstituted or substituted aryl radical, and n is 4, 5, or 6, which can be converted into a compound of Formula A. Again, similar to the previous processes, this process requires a large number of synthetic steps to obtain a compound of Formula A. Finally, all of the previous processes require as the penultimate step conversion of an intermediate salt of the target compound to an amino acid of Formula A.

U.S. Pat. Nos. 5,132,451, 5,319,135, 5,362,883, 5,091,567, 5,068,413, 4,956,473, 4,958,044, 5,130,455, 5,095,148, 5,136,091, and 5,149,870 disclose additional processes and intermediates for preparing gabapentin. These processes require a number of steps and in some cases utilize large quantities of hazardous materials.

The object of the present invention is an improved process for preparing gabapentin employing a novel synthesis.

Further, we have unexpectedly found that gabapentin can be prepared from novel intermediates in fewer steps and higher yields than the previous methods. Moreover, the present method proceeds from inexpensive starting materials and is amenable to large-scale synthesis.

SUMMARY OF THE INVENTION

Accordingly, a first aspect of the present invention is an improved process for the preparation of the compound of Formula I

which comprises:

Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula V

 wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV

 wherein R is as defined above;

Step (c) treating a compound of Formula IVa

wherein R^(1a) is alkyl with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula III

 wherein R^(1a) is as defined above;

Step (d) treating the compound of Formula IIIa

 with an acid in a solvent to afford the compound of Formula II

 or treating a compound of Formula IIIb

 wherein R^(1b) is alkyl excluding tertiary butyl with an acid or base in a solvent to afford the compound of Formula II or treating the compound of Formula IVb

 with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula II or treating the compound of Formula IVc

 with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula II;

Step (e) treating the compound of Formula IVa-1

 with an acid in a solvent to afford the compound of Formula IVb or treating a compound of Formula IVa-2

 wherein R^(1a-2) is alkyl excluding tertiary butyl with an acid or base in a solvent to afford the compound of Formula IVb; and

Step (f) treating either the compound of Formula IVb or the compound of Formula IVc or the compound of Formula II with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula I.

A second aspect of the present invention is an improved process for the preparation of a compound of Formula IV

wherein R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl which comprises:

Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula V

 wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV.

A third aspect of the present invention is an improved process for the preparation of a compound of Formula III

wherein R^(1a) is alkyl which comprises:

Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula V

 wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV

 wherein R is as defined above; and

Step (c) treating a compound of Formula IVa

 wherein R^(1a) is alkyl with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula III.

A fourth aspect of the present invention is an improved process for the preparation of the compound of Formula II

which comprises:

Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula V

 wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV

 wherein R is as defined above;

Step (c) treating a compound of Formula IVa

 wherein R^(1a) is alkyl with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula III

 wherein R^(1a) is as defined above; and

Step (d) treating the compound of Formula IIIa

 with an acid in a solvent to afford the compound of Formula II or treating a compound of Formula IIIb

 wherein R^(1b) is alkyl excluding tertiary butyl with an acid or base in a solvent to afford the compound of Formula II or treating the compound of Formula IVb

 with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula II or treating the compound of Formula IVc

 with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula II.

A fifth aspect of the present invention is an improved process for the preparation of the compound of Formula IVb

which comprises:

Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula IVa

 wherein X is halo or sulfonate and R^(1a) is alkyl, in the presence of a solvent to afford a compound of Formula IVa

 wherein R^(1a) is as defined above; and

Step (c) treating a compound of Formula IVa with an acid or base in a solvent to afford the compound of Formula IVb

A sixth aspect of the present invention is an improved process for the preparation of the compound of Formula I

which comprises:

Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula VIII

 wherein X is halo or sulfonate and R² is alkyl in the presence of a solvent to afford a compound of Formula IX

 wherein R² is alkyl;

Step (c) treating a compound of Formula IX with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula X

 wherein R² is as defined above;

Step (d) treating a compound of Formula IX with an acid in the presence of a solvent to afford the compound of Formula IVb

 or treating a compound of Formula X with an acid in the presence of a solvent to afford the compound of Formula II

Step (e) treating either the compound of Formula IVb or Formula II with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula I

A seventh aspect of the present invention is an improved process for the preparation of a compound of Formula IX

wherein R² is alkyl which comprises:

Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula VIII

 wherein X is halo or sulfonate and R² is alkyl in the presence of a solvent to afford a compound of Formula IX.

An eighth aspect of the present invention is an improved process for the preparation of a compound of Formula X

wherein R² is alkyl which comprises:

Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula VIII

 wherein X is halo or sulfonate and R² is alkyl in the presence of a solvent to afford a compound of Formula IX

 wherein R² is alkyl; and

Step (c) treating a compound of Formula IX with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula X.

A ninth aspect of the present invention is an improved process for the preparation of the compound of Formula II

which comprises:

Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula VIII

 wherein X is halo or sulfonate and R² is alkyl in the presence of a solvent to afford a compound of Formula IX

 wherein R² is alkyl;

Step (c) treating a compound of Formula IX with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula X

 wherein R² is as defined above; and

Step (d) treating a compound of Formula X with an acid in the presence of a solvent to afford the compound of Formula II.

A tenth aspect of the present invention is an improved process for the preparation of the compound of Formula IVb

which comprises:

Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula VIII

 wherein X is halo or sulfonate and R² is alkyl in the presence of a solvent to afford a compound of Formula IX

 wherein R² is alkyl; and

Step (c) treating a compound of Formula IX with an acid in the presence of a solvent to afford the compound of Formula IVb

An eleventh aspect of the present invention is a novel compound of Formula IV

wherein R¹ is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl.

A twelfth aspect of the present invention is a novel compound of Formula IX

wherein R² is alkyl.

A thirteenth aspect of the present invention is a novel compound of Formula X

wherein R² is alkyl.

DETAILED DESCRIPTION OF THE INVENTION

In this invention, the term “alkyl” means a straight or branched hydrocarbon group having from one to twelve carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl n-butyl, isobutyl, tertiary-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, and the like.

“Alkali metal” is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium, and the like.

“Alkaline-earth metal” is a metal in Group IIA of the periodic table and includes, for example, calcium, barium, strontium, magnesium, and the like.

“Halo” is halogen which is fluorine, chlorine, bromine, or iodine.

“Sulfonate” is tosyl, mesyl, phenylsulfonate, chlorophenylsulfonate, bromophenylsulfonate, methoxyphenylsulfonate, and the like.

“Higher order amine” is methylamine, dimethylamine, methylethylamine, diethylamine, and the like.

“Amine cation” is

wherein R, R¹, R², R³, are the same or different and each is hydrogen, alkyl of from 1 to 8 carbon atoms, phenyl, tolyl, and the like.

The compounds of Formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of thee forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M., et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977;66:1-19).

The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free bases for purposes of the present invention.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethmolamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge S. M., supra.).

The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acids for purposes of the present invention.

Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

U.S. Pat. Nos. 4,894,476 and 4,960,931 disclose gabapentin monohydrate and a process for producing the gabapentin monohydrate.

The following table provides a list of abbreviations and definitions thereof used in the present invention:

DEFINITION ABBREVIATION Tertiary butyl alcohol t-BuOH Ammonia NH₃ Trifluoroacetic acid TFA Tetrahydrofuran THF Nitrogen N₂ Ethyl acetate EtOAc Magnesium sulfate MgSO₄ Dichloromethane CH₂Cl₂ Proton nuclear magnetic resonance spectroscopy ¹H-NMR Deuterated chloroform CDCl₃ Carbon nuclear magnetic resonance spectroscopy ¹³C-NMR Methanol MeOH Hydrogen H₂ Methyl tertiary butyl ether MTBE Hydrochloric acid HCl Palladium on charcoal Pd/C Ammonium hydroxide NH₄OH Deuterated methanol CD₃OD Silicon dioxide (silica) SiO₂ Palladium on barium sulfate Pd/BaSO₄ Vapor phase chromatography VPC Pounds per square inch PSI Potassium hydroxide KOH Sodium hydroxide NaOH Potassium bromide KBr Ethanol EtOH tertiary Butyl t-Bu Benzyl Bn Refractive index high performance liquid RI HPLC chromatography Infrared spectroscopy IR Deuterium oxide D₂O Water H₂O Thin layer chromatography TLC

Preferred compounds of Formula IV prepared by the improved process of the first aspect of the present invention are:

(1-Cyanocyclohexa-2,5-dienyl)acetic acid ethyl ester;

(1-Cyanocyclohexa-2,5-dienyl)acetic acid;

(1-Cyanocyclohexa-2,5-dienyl)acetic acid benzyl ester; and

(1-Cyanocyclohexa-2,5-dienyl)acetic acid t-butyl ester;

or a pharmaceutically acceptable salt thereof.

Preferred compounds of Formula IX prepared by the improved process of the fifth aspect of the present invention are:

1-(2,2,2-Trimethoxy-ethyl)-cyclohexa-2,5dienecarbonitrile;

1-(2,2,2-Triethoxy-ethyl)-cyclohexa-2,5-dienecarbonitrile; and

1-(2,2,2-Triisopropoxy-ethyl)-cyclohexa-2,5-dienecarbonitrile.

Preferred compounds of Formula X prepared by the improved process of the fifth aspect of the present invention are:

1-(2,2,2-Trimethoxy-ethyl)-cyclohexanecarbonitrile;

1-(2,2,2-Triethoxy-ethyl)cyclohexanecarbonitrile; and

1-(2,2,2-Triisopropoxy-ethyl)-cyclohexanecarbonitrile.

As previously described, the compound of Formula I is useful for the treatment of certain forms of epilepsy, faintness attacks, hypokinesia, and cranial trauma.

The process of the present invention in its first aspect is a new, improved, economical, and commercially feasible method for preparing the compound of Formula I. Furthermore, the process can be carried out in a two-pot procedure.

The process of the present invention in its first aspect is outlined in Scheme 1.

A compound of Formula IV is prepared from benzonitrile (VII) using a Birch reduction, i.e., dissolving metal reduction methodology followed by subsequent alkylation of the anionic intermediate (VI) which is generated in situ.

The alkylation of anions generated in Birch reductions is an established methodology (see “Organic Reactions”, ed. Paquette L. A., et al., John Wiley & Sons, New York, N.Y., 1992;42:1-334) in organic synthesis. However, there is only one report of the reductive alkylation of benzonitrile (Schultz A. G. and Macielag M., Journal of Organic Chemistry, 1986;51:4983). There is no disclosure of alkylation of these intermediate anions with α-halo acetic acid esters. Though alkylation of nitrites has been disclosed (“Organic Reactions”, ed. Dauben W. G., et al., John Wiley & Sons. New York, N.Y., 1984:31:1-364), the alkylation of cyclohexanecarbonitrile and cyclohexanecarbonitrile type compounds with α-halo acetic acid esters has not been reported. We have unexpectedly and surprisingly found that the Birch reduction anionic intermediate (VI) is successfully alkylated with α-haloacetic acid and α-haloacetic acid esters in high yields.

Thus, a solution of benzonitrile in a solvent such as, for example, an alcohol such as tertiary butyl alcohol, ethanol, isopropyl alcohol, tetrahydrofuran, diethyl ether, methyl tertiary butyl ether (MTBE) and the like is treated with an alkali metal such as, for example, lithium, sodium, potassium, and the like an amine such as, for example, ammonia and the like at about −78° C. to about −33° C. for about 0.5 to about 8 hours to generate in situ the anionic intermediate (VI) followed by subsequent treatment with a compound of Formula V wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl to afford a compound of Formula IV wherein R is hydrogen, alkyl, or benzyl. Preferably, the reaction is carried out with lithium in ammonia in tertiary butyl alcohol and tetrahydrofuran.

A compound of Formula IVa wherein R (R^(1a)) is alkyl is treated with hydrogen in the presence of a catalyst such as, for example, rhodium on carbon containing palladium, rhodium on carbon containing platinum, rhodium on calcium carbonate containing palladium, rhodium on alumina containing palladium, palladium on carbon, palladium on carbon in the presence of a mineral acid, Raney nickel, and Raney cobalt and the like and a solvent such as, for example, methanol and the like to afford a compound of Formula III wherein R^(1a) is alkyl. Preferably, the reaction is carried out with palladium on charcoal and methanol.

A compound of Formula IIIa (R^(1a) is tertiary butyl [t-Bu]) is treated with an acid such as, for example, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, hydrobromic acid in acetic acid, formic acid, para toluenesulfonic acid, and the like in a solvent such as, for example, dichloromethane, toluene, diethyl ether and the like to afford the compound of Formula II. Preferably, the reaction is carried out with trifluoroacetic acid in dichloromethane.

A compound of Formula IIIb (R^(1a) is alkyl excluding tertiary butyl) is treated with an acid such as, for example, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, paratoluenesulfonic acid and the like or a base such as, for example, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like or an alkaline earth metal hydroxide, such as calcium hydroxide and the like in a solvent such as, for example, water and/or an alcohol such as methanol, ethanol and the like to afford the compound of Formula II. Preferably, the reaction is carried out with potassium hydroxide in ethanol.

A compound of Formula IVc (R is benzyl [Bn]) is treated with hydrogen in the presence of a catalyst using the conditions previously described for preparing a compound of Formula III from a compound of Formula IVa to afford the compound of Formula II.

The compound of Formula IVa-1 (R¹ is t-Bu) is treated with an acid in the presence of a solvent using the conditions previously described for preparing a compound of Formula II from the compound of Formula IIIa to afford the compound of Formula IVb.

The compound of Formula IVa-2 (R¹ is alkyl excluding t-Bu) is treated with an acid or base in the presence of a solvent using the conditions previously described for preparing the compound of Formula II from a compound of Formula IIIb to afford the compound of Formula IVb.

The compound of Formula IVb is treated with hydrogen in the presence of a catalyst using the conditions previously described for preparing a compound of Formula III from a compound of Formula IVa to afford the compound of Formula II.

The compound of Formula IVb, or the compound of Formula IVc, or the compound of Formula II is treated with hydrogen in the presence of a catalyst and a solvent using the conditions previously described for preparing a compound of Formula III from a compound of Formula IVa to afford the compound of Formula I.

The process of the present invention in its fifth aspect is a new, improved, economical, and commercially feasible method for preparing the compound of Formula I. The process of the present invention in its fifth aspect is outlined in Scheme 2.

Thus, the anionic intermediate (VI) is generated in situ as described above followed by subsequent treatment with a compound of Formula VIII wherein X is halo or sulfonate and R² is alkyl using the conditions previously described for preparing a compound of Formula IV from the compound of Formula VI to afford a compound of Formula IX wherein R² is as defined above.

A compound of Formula IX is treated with hydrogen in the presence of a catalyst and a solvent using the conditions previously described for preparing a compound of Formula III from a compound of Formula IVa to afford a compound of Formula X wherein R² is as defined above.

A compound of Formula IX is treated with an acid such as, for example, formic acid, acetic acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, para toluenesulfonic acid and the like in a solvent such as, for example, dichloromethane, toluene, tetrahydrofuran, diethyl ether and the like to afford the compound of Formula IVb. Preferably, the reaction is carried out with hydrochloric acid in dichloromethane.

A compound of Formula X is treated with an acid in a solvent using the conditions previously described for preparing the compound of Formula IVb from a compound of Formula IX to afford the compound of Formula II.

The compound of Formula IVb or Formula II is treated with hydrogen in the presence of a catalyst and a solvent using the conditions previously described for preparing a compound of Formula III from a compound of Formula IVa to afford the compound of Formula I.

Compounds of Formula V and Formula VIII are either known or capable of being prepared by methods known in the art.

The following nonlimiting examples illustrate the inventors' preferred method for preparing the compound of the invention.

EXAMPLE 1 1-(Aminomethyl)-cyclohexaneacetic acid

Method A

Step A: Preparation of(1-Cyanocyclohexa-2,5-dienyl)acetic acid ethyl ester

Lithium (0.17 g, 24 mmol) was added in portions to a solution of benzonitrile (0.99 mL, 1.0 g, 9.7 mmol) and t-BuOH (0.93 mL, 0.72 g, 9.7 mmol) in NH₃ (50 mL) and THF (10 mL) under N₂ at −78° C. After 10 minutes, ethyl bromoacetate (2.2 mL, 3.3 g, 20 mmol) was added dropwise. After 1 hour, ammonium chloride (4.0 g, 75 mmol) was added in portions. The reaction mixture was slowly warmed to room temperature while the NH₃ was removed with a stream of N₂. Water (25 mL) was added, and the mixture extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO₄), and concentrated under reduced pressure. Flash chromatography (SiO₂, CH₂Cl₂) afforded 1.12 g (60%) of product as an oil.

¹H-NMR (CDCl₃): δ 1.28 (t, J=7.1 Hz, 3H), 2.71 (m, 4H), 4.20 (q, J=7.1 Hz, 2H), 5.82 (dt, J=1.9, 10.1 Hz, 2H), 6.01 (dt, J=3.3, 10.1 Hz, 2H);

¹³C-NMR (CDCl₃): δ 14.2, 25.7, 34.4, 45.1, 61.2, 120.5, 123.6, 128.0, 168.3;

IR (neat) 2984, 2231, 1736, 1185 cm⁻¹.

Step B: Preparation of (1-Cyanocyclohexyl)acetic acid ethyl ester

Added 1% Pd/C catalyst (1.67 g, 0.157 mmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid ethyl ester (3.00 g, 15.7 mmol) in MeOH (75 mL). After shaking the reaction under 20 psi H₂ at room temperature for 2 hours, the pressure was slowly released. The reaction was filtered and concentrated under reduced pressure to afford 2.89 g (94%) of product as an oil.

¹H-NMR (CDCl₃): δ 1.10-1.55 (m, 5H, inc. 1.29, t, J=7.1 Hz), 1.72 (m, 6H), 2.05-2.18 (m, 2H), 2.55 (s, 2H), 4.20 (q, J=7.1 Hz, 2H);

¹³C-NMR (CDCl₃): δ 14.3, 22.9, 25.2, 35.6, 36.7, 44.5, 61.1, 122.4, 169.1.

Step C: Preparation of (1-Cyanocyclohexyl)acetic acid

(1-Cyanocyclohexyl)acetic acid ethyl ester is reacted with aqueous sodium hydroxide solution using the methodology disclosed at Column 15, Method C, Step B of U.S. Pat. No. 5,132,451 which is herein incorporated by reference to afford the title product.

Step D: Preparation of 1-(Aminomethyl)-cyclohexaneacetic acid

(1-Cyanocyclohexyl)acetic acid is hydrogenated using the methodology disclosed at Columns 14 to 15, Method B, of U.S. Pat. No. 5,132,451 to afford the title compound.

Method B

Step A: Preparation of (1-Cyanocyclohexa-2,5-dienyl)acetic acid

Lithium (0.87 g, 125 mmol) was added in portions to a stirred solution of benzonitrile (5.1 mL, 5.2 g, 50 mmol) and t-BuOH (4.8 mL, 3.7 g, 50 mmol) in THF (5 mL) and NH₃ (25 mL). After stirring at −78° C. for 30 minutes, a solution of bromoacetic acid ammonium salt (prepared by mixing bromoacetic acid [13.90 g, 100.0 mmol], THF (15 mL), and N₂ (50 mL) at −78° C. and stirring for 1.5 hours) was added dropwise to the reaction. After stirring at −78° C. for 1 hour, ammonium chloride (20.9 g, 391 mmol) was added in portions. The reaction mixture was slowly warmed to room temperature while the NH₃ was removed with a stream of N₂. Water (75 mL) was added, and the mixture extracted with MTBE (3×50 mL). The stirred aqueous layer was cooled to 0-5° C. acidified to pH=1 with 37% HCl, and extracted with MTBE (3×50 mL). The combined organic extracts of the acidified aqueous layer were dried (MgSO₄) and concentrated under reduced pressure to afford 2.49 g (31%) of product as a white solid.

¹H-NMR (CDCl₃): δ 2.72 (m, 2H), 2.78 (s, 2H), 5.84 (dt, J=1.9, 10.2 Hz, 2H), 6.03 (dt, J=3.3, 10.1 Hz, 2H), 10.41 (broad s, 1H);

¹³C-NMR(CDCl₃): δ 25.7, 34.2, 44.9, 120.5, 123.4, 128.4, 174.1;

IR(KBr) 3051, 2915, 2235, 1719, 1248 cm⁻¹.

Step B: Preparation of (1-Cyanocyclohexyl)acetic acid

Added 5% Pd/C catalyst (0.65 g, 0.31 mmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid (0.50 g, 3.1 mmol) and 28% NH₄OH (42.5 μL, 38.3 μg, 0.31 mmol) in MeOH (15 mL). After shaking the reaction mixture under 50 psi H₂ at room temperature for 1 hour, the pressure was slowly released. The reaction was filtered and concentrated under reduced pressure to afford 0.48 g (94%) of crude product.

¹H-NMR (CD₃OD): δ 1.03-1.59 (m, 7H, theo. 3H), 1.59-1.86 (m, 4H, theo. 5H), 1.96-2.12 (m, 2H), 2.47 (s, 2H), 4.86 (s, 4H, theo. 1H);

RI HPLC 63% area.

Step C: Preparation of 1-(Aminomethyl)-cyclohexaneacetic acid

The title compound is prepared as described in Method A, Step D.

Method C

Step A: Preparation of (1-Cyanocylcohexa-2,5-dienyl)acetic acid benzyl ester

Lithium (0.17 g, 24 mmol) was added in portions to a stirred solution of benzonitrile (0.99 mL, 1.0 g, 9.7 mmol) and t-BuOH (0.93 mL. 0.72 g, 9.7 mmol) in NH₃ (50 mL) and THF (10 mL) under N₂ at −78° C. After stirring for 15 minutes, benzyl-2-bromoacetate (3.1 mL, 4.5 g, 20 mmol) was added dropwise. After 1 hour, ammonium chloride (4.0 g, 75 mmol) was added in portions. The reaction mixture was slowly warmed to room temperature while the NH₃ was removed with a stream of N₂. Water (25 mL) was added, and the mixture extracted with EtOAc (3×5 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO₄), and concentrated under reduced pressure. Flash chromatography (SiO₂, 1:1-3:1 CH₂Cl₂:hexane) afforded 1.79 g (73%) of product as an oil.

¹H-NMR (CDCl₃): δ 2.60-2.71 (m, 2H), 2.77 (s, 2H), 5.17 (s, 2H), 5.79 (dt, J=1.8, 10.0 Hz, 2H), 5.97 (dt, J=3.3, 9.8 Hz, 2H), 7.37 (m, 5H);

¹³C-NMR (CDCl₃): δ 25.6, 34.4, 45.0, 67.0, 120.5, 123.4, 128.1, 128.5, 128.6, 128.9, 135.5, 168.1;

IR (neat) 3035, 2233, 1738, 1170 cm⁻¹.

Step B: Preparation of (1-Cyanocyclohexyl)acetic acid

Added 5% Pd/BaSO₄ catalyst (9.0 mg, 4.2 μmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid benzyl ester (1.00 g, 3.95 mmol) in MeOH (20 mL). After stirring the reaction mixture under an atmosphere of H₂ at 0° C. for 0.5 hour and room temperature for 1.5 hours, additional 5% Pd/BaSO₄ (75.8 mg, 35.6 μmol) was added. After stirring the reaction mixture under an atmosphere of H₂ at 0° C. for 1 hour and room temperature for 19.5 hours, the reaction was filtered and concentrated under reduced pressure to afford 0.56 g (87%) of crude oil.

¹H-NMR (CD₃OD) complex mix showing majority of product;

VPC assay 43% area;

RI HPLC assay 40% area.

Step C: Preparation of 1-(Aminomethyl)-cyclohexaneacetic acid

(1-Cyanocyclohexyl)acetic acid is hydrogenated according to the procedure of Method A, Step D to afford the title compound.

Method D

Step A: Preparation of (1-Cyanocyclohexa-2,5-dienyl)acetic acid t-butyl ester

Lithium (1.73 g, 249 mmol) was added in portions to a stirred solution of benzonitrile (10.2 mL, 10.3 g, 99.9 mmol) and t-BuOH (9.6 mL, 7.4 g, 100 mmol) in NH₃ (50 mL) and THF (10 mL) under N₂ at −78° C. After stirring for 25 minutes, t-butyl bromoacetate (29.5 mL, 39.0 g, 200 mmol) was added dropwise. After 1 hour, ammonium chloride (41.8 g, 781 mmol) was added in portions. The reaction mixture was slowly warmed to room temperature while the NH₃ was removed with a stream of N₂. Water (125 mL) was added and the mixture extracted with MTBE (3×50 mL). The combined organic extracts were dried (MgSO₄) and concentrated under reduced pressure. Flash chromatography (SiO₂, CH₂Cl₂-1:14 MTBE:CH₂Cl₂) afforded 16.0 g (73%) of product as an oil.

¹H-NMR (CDCl₃): δ 1.48 (s, 9H), 2.61 (s, 2H), 2.67-2.76 (m, 2H), 5.80 (dt, J=1.9, 10.3 Hz, 2H), 5.99 (dt, J=3.3, 10.2 Hz, 2H);

¹³C-NMR (CDCl₃): δ 25.6, 28.1, 34.5, 46.3, 82.0, 120.6, 123.8, 127.7, 167.5;

IR (neat) 2980, 2232, 1729, 1153 cm¹.

Step B: Preparation of (1 -Cyanocyclohexyl)acetic acid t-butyl ester

Added 5% Pd/C, 50% H₂O catalyst (94.0 mg, 22.1 μmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid t-butyl ester (0.50 g, 2.3 mmol) in MeOH (10 mL). After shaking the reaction mixture under 20 psi H₂ at room temperature for 18.5 hours, the pressure was slowly released. The reaction was filtered and concentrated under reduced pressure. Flash chromatography (SiO₂, 1:3 hexane:CH₂Cl₂-100% CH₂Cl₂) afforded 0.29 g (56%) of product as an oil.

¹H-NMR (CDCl₃): δ 1.10-1.45 (m, 4H), 1.49 (s, 9H), 1.60-1.89 (m, 4H), 1.95-2.21 (m, 2H), 2.45 (s, 2H);

¹³C-NMR (CDCl₃): δ 22.9, 25.2, 28.2, 35.7, 36.8, 45.7, 81.9, 122.6. 168.6;

IR (neat) 2935, 2234, 1729, 1368, 1149 cm⁻¹.

Step C: Preparation of (1-Cyanocyclohexyl)acetic acid

To a solution of 2.4 mL (2.4 g, 22 mmol) of anisole in 50 mL of trifluoroacetic acid is added 5.00 g (22.4 mmol) of (1-cyanocyclohexyl)acetic acid, 1-butyl ester. The reaction is monitored (TLC) for the loss of starting material and when the reaction is complete it is concentrated under reduced pressure. Water (˜10 mL) is added to the residue and the mixture is adjusted to pH=10-12 with base (NaOH). The basic aqueous layer is extracted with a suitable organic solvent (EtOAc) to remove impurities. The aqueous layer is acidified with acid (HCl) to pH=0-4 and extracted with a suitable solvent (EtOAc). The combined organic extracts of the acidified aqueous layer are dried and concentrated under reduced pressure to afford the product.

Step D: Preparation of 1-(Aminomethyl)cyclohexaneacetic acid

(1-Cyanocyclohexyl)acetic acid is hydrogenated according to the procedure of Method A, Step D to afford the title compound.

Method E

Step A: Preparation of (1-Cyanocyclohexa-2,5-dienyl)acetic acid

Method a

Added dropwise a solution of KOH (1.73 M, 5.0 mL, 8.7 mmol) in 1:4 H₂O:2B EtOH to a stirred solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid ethyl ester (3.00 g, 15.7 mmol) in 2B EtOH (15 mL) at 0° C. After stirring for 1 hour, a solution of KOH (1.73 M, 5.0 mL, 8.7 mmol) in 1:4 H₂O:2B EtOH was added dropwise. After stirring for 2.5 hours, the reaction was concentrated under reduced pressure. Water (5 mL) was added, and the mixture was extracted with CH₂Cl₂ (3×10 mL). The aqueous layer was cooled to 5° C. and acidified to pH=3 with 37% HCl (1.1 mL, 13.4 mmol). The solids were filtered, washed with H₂O (pH=5), and dried under vacuum at room temperature for 16 hours to afford 1.57 g (61%) of the product as a solid.

¹H-NMR (CDCl₃): δ 2.73 (m, 2H), 2.78 (s, 2H), 5.83 (dt, J=1.9, 10.3 Hz, 2H), 6.03 (dt, J=3.4, 10.4 Hz, 2H), 9.27 (broad s, 1H);

¹³C-NMR: δ 25.8, 34.3, 44.8, 120.5, 123.4, 128.4, 173.8.

Method b

To a solution of 2.5 mL (2.5 g, 23 mmol) of anisole in 50 mL of trifluoroacetic acid is added 5.00 g (22.8 mmol) of (1-cyanocyclohexa-2,5-dienyl) acetic acid, t-butyl ester. The reaction is monitored (TLC) for the loss of starting material and when the reaction is complete it is concentrated under reduced pressure. Water (˜10 mL) is added to residue and the mixture is adjusted to pH=10-12 base (NaOH). The basic aqueous layer is extracted with a suitable organic solvent (EtOAc) to remove impurities. The aqueous layer is acidified with acid (HCl) to pH=0.4 and extracted with a suitable solvent (EtOAc). The combined organic extracts of the acidified aqueous layer are dried and concentrated under reduced pressure to afford the product.

Step B: Preparation of 1-(Aminomethyl)cyclohexaneacetic acid

Added 5% Pd/C catalyst (0.33 g, 0.16 mmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid (0.25 g, 1.5 mmol) and 28% NH₄OH (70 μL, 63 μg, 0.50 mmol) in MeOH (20 mL). After shaking the reaction mixture under 50 psi H₂ at 50° C. for 3.5 hours, the pressure was slowly released, and the reaction was cooled to room temperature. The reaction was filtered and concentrated under reduced pressure to afford 0.27 g (102%) of crude product.

¹H-NMR (D₂O ): δ 1.46 (m, 11H, theo. 10H), 2.43 (s, 2H), 3.00 (s, 2H), 4.78 (s, 4H, theo. 3H);

¹³C-NMR (D₂O): δ 20.5, 24.8, 33.0, 33.8, 45.4, 47.8, 179.8.

Method F

Preparation of 1-(Aminomethyl)cyclohexaneacetic acid

Added 5% Pd/C catalyst (0.84 g, 0.40 mmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid benzyl ester (1.00 g, 3.95 mmol) and 28% NH₄OH (0.55 mL, 0.50 g, 4.0 mmol) in MeOH (20 mL). After shaking the reaction mixture under 50 psi H₂ at 50° C. for 18 hours, the pressure was slowly released, and the reaction was cooled to room temperature. The reaction was filtered and concentrated under reduced pressure to afford 0.63 g (93%) of crude product.

¹H-NMR (CD₃OD): δ 1.51 (m, 11H, theo. 10H), 2.45 (s, 2H), 2.89 (s, 2H), 4.94 (s, 9H, theo. 3H);

RI HPLC 68% area.

Method G

Step A: Preparation of (1-Cyanocyclohexa-2,5-dienyl)acetic acid

The title compound is prepared as described in Method B, Step A.

Step B: Preparation of 1-(Aminomethyl)cyclohexaneacetic acid

The title compound is prepared as described in Method E, Step B.

Method H

Step A: Preparation of (1-Cyanocyclohexa-2,5-dienyl)acetic acid ethyl ester

The title compound is prepared as described in Method A, Step A.

Step B: Preparation of (1-Cyanocyclohexa-2,5-dienyl)acetic acid

The title compound is prepared as described in Method E, Step A.

Step C: Preparation of (1-Cyanocyclohexyl)acetic acid

The title compound is prepared as described in Method B, Step B.

Step D: Preparation of 1-(Aminomethyl)cyclohexaneacetic acid

The title compound is prepared as described in Method A, Step D. 

What is claimed is:
 1. A process for the preparation of a compound of Formula IV

wherein R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl which comprises: Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula V

 wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV.
 2. A process for the preparation of the compound of Formula IVb

which comprises: Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula Va

 wherein X is halo or sulfonate and R^(1a) alkyl in the presence of a solvent to afford a compound of Formula IVa

 wherein R^(1a) is as defined above; and Step (c) treating a compound of Formula IVa with an acid or base in a solvent to afford the compound of Formula IVb.
 3. A compound of Formula IV

wherein R¹ is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl.
 4. A compound selected from the group consisting of: (1-Cyanocyclohexa-2,5-dienyl)acetic acid ethyl ester; (1-Cyanocyclohexa-2,5-dienyl)acetic acid; (1-Cyanocyclohexa-2,5-dienyl)acetic acid benzyl ester; and (1-Cyanocyclohexa-2,5-dienyl)acetic acid t-butyl ester; or a pharmaceutically acceptable salt thereof.
 5. A process for the preparation of a compound of Formula IX

wherein R² is alkyl which comprises: Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula VIII

wherein X is halo or sulfonate and R² is alkyl in the presence of a solvent to afford a compound of Formula IX.
 6. A process for the preparation of a compound of Formula X

wherein R² is alkyl which comprises: Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula VIII

 wherein X is halo or sulfonate and R² is alkyl in the presence of a solvent to afford a compound of Formula IX

 wherein R² is alkyl; and Step (c) treating a compound of Formula IX with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula X.
 7. A process for the preparation of the compound of Formula IVb

which comprises: Step (a) treating the compound of Formula VII

 with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI

Step (b) treating the compound of Formula VI with a compound of Formula VIII

 wherein X is halo or sulfonate and R² is alkyl in the presence of a solvent to afford a compound of Formula IX

 wherein R² is alkyl; and Step (c) treating a compound of Formula IX with an acid in the presence of a solvent to afford the compound of Formula IVb.
 8. A compound of Formula IX

wherein R² is alkyl.
 9. A compound according to claim 8 selected from the group consisting of: 1-(2,2,2-Trimethoxy-ethyl)-cyclohexa-2,5-dienecarbonitrile; 1-(2,2,2-Triethoxy-ethyl)-cyclohexa-2,5-dienecarbonitrile; and 1-(2,2,2-Triisopropoxy-ethyl)-cyclohexa-2,5-dienecarbonitrile.
 10. A compound of Formula X

wherein R² is alkyl.
 11. A compound according to claim 10 selected from the group consisting of: 1-(2,2,2-Trimethoxy-ethyl)-cyclohexanecarbonitrile; 1-(2,2,2-Triethoxy-ethyl)-cyclohexanecarbonitrile; and 1-(2,2,2-Triisopropoxy-ethyl)-cyclohexanecarbonitrile. 